Plasmodium falciparum malaria is more severe in pregnant women, especially during the first pregnancy (primigravida), and causes disease in the mother and fetal death even in those women who were previously immune. (Steketee, et al., Am J Trop Med Hyg 55, 2-7 (1996)). In the primigravida, massive numbers of parasitized red blood cells (PRBCs) sequester in the maternal circulation of the placenta, binding to chondroitin sulfate A (CSA). (Fried & Duffy, Science 272, 1502-1504 (1996)). Antibodies that develop after multiple pregnancies are associated with reduced PRBCs in the placenta and block CSA-binding of PRBCs. (Fried, et al., Nature 395, 851-2 (1998)).
Members of the recently described var gene family and their expressed proteins, Plasmodium falciparum Erythrocyte Membrane Protein-I (PfEMP1), mediate PRBCs binding to several adhesion receptors such as CD36, intercellular adhesion molecule-1 (ICAM-1), and chondroitin sulfate A (CSA). (Baruch, et al., Cell 82, 77-87 (1995), (Smith, et al., Cell 82, 101-10 (1995), (Su, et al., Cell 82, 89-100 (1995), and (Scherf, et al., Embo J 17, 5418-5426 (1998)). Recent work on var gene switching has established that transcription of a particular var gene (termed “FCR3.varCSA”) in parasites selected for binding to CSA but not in parasites selected for adhesion to CD36 or ICAM-1. (Scherf, et al., Embo J 17, 5418-5426 (1998)). Thus, var genes adhere dichotomously either to CD36 and other receptors on endothelium or to CSA in placenta and not to CD36.
Potential receptor domains in var genes include Duffy binding like (DBL) domains, named for their homology to the Duffy binding domain of P. vivax (Su, et al., Cell 82, 89-100 (1995)), and cysteine-rich interdomain regions (CIDR). The CIDR1 domain, located after the first DBL, was shown to mediate PRBCs adhesion to CD36. (Baruch, et al., Cell 82, 77-87 (1995) and (Baruch, et al., Blood 90, 3766-75 (1997)). DBL1 has been identified as a receptor for binding PRBCs to uninfected RBCs in var genes from PRBCs that rosette normal RBCs. (Rowe, et al., Nature 388, 292-5 (1997) and (Chen, et al., J Exp Med 187, 15-23 (1998)). Although antibodies directed to two different domains of a var gene expressed in CSA-binding parasites reduced binding to CSA (Reeder, et al., Proc Natl Acad Sci USA 96, 5198-202 (1999)), the gene, protein and domains thereof that bind CSA have not been identified.